Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Original ArticlesCystic Kidney Disease
You have accessRestricted Access

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

Jens König, Birgitta Kranz, Sabine König, Karl Peter Schlingmann, Andrea Titieni, Burkhard Tönshoff, Sandra Habbig, Lars Pape, Karsten Häffner, Matthias Hansen, Anja Büscher, Martin Bald, Heiko Billing, Raphael Schild, Ulrike Walden, Tobias Hampel, Hagen Staude, Magdalena Riedl, Norbert Gretz, Martin Lablans, Carsten Bergmann, Friedhelm Hildebrandt, Heymut Omran and Martin Konrad; for the Gesellschaft für Pädiatrische Nephrologie (GPN)
CJASN December 2017, 12 (12) 1974-1983; DOI: https://doi.org/10.2215/CJN.01280217
Jens König
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Birgitta Kranz
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sabine König
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karl Peter Schlingmann
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrea Titieni
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Burkhard Tönshoff
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandra Habbig
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lars Pape
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karsten Häffner
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias Hansen
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anja Büscher
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Bald
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heiko Billing
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raphael Schild
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ulrike Walden
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tobias Hampel
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hagen Staude
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Magdalena Riedl
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Norbert Gretz
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Lablans
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carsten Bergmann
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Friedhelm Hildebrandt
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heymut Omran
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Konrad
Due to the number of contributing authors, the affiliations are provided in the .
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Figure1
    • Download figure
    • Open in new tab
    • Download powerpoint
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    Chronic kidney disease and polyuria are the clinical hallmarks for NPHP1 patients while the main signs and symptoms for children with other NPHP mutations can be manifold. Initial clinical presentation leading to the diagnosis of nephronophthisis (NPH) or NPH-related ciliopathies in the Nephronophthisis Registry. Although in one half of the children with NPHP1, polyuria (54%) or CKD (46%) led to diagnosis, the main signs and symptoms of children without NPHP1 were less specific, including dysmorphic features (11%), failure to thrive (18%), developmental delay (18%), visual impairment (12%), or fetal tachypnoe (10%). However, the latter symptoms presented significantly earlier, mostly within the first year of life, whereas the first signs of urinary-concentrating defects usually did not become obvious before the age of 4–6 years old. COMA, congenital oculomotor apraxia.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    Isolated NPH is the typical phenotype of most NPHP1 patients while complex NPH-related ciliopathies are abundant in the nonNPHP1 group. Frequency of clinically defined nephronophthisis (NPH)-related ciliopathies in the Nephronophthisis Registry with respect to the presence/absence of an NPHP1 deletion. Isolated NPH is more frequent in (A) the NPHP1 group than in (B) children without NPHP1. Nevertheless, in 25%, a homozygous NPHP1 deletion led to a neurologic phenotype as well. (C) Axial magnetic resonance image of a child with Joubert syndrome showing the typical cerebellar vermis hypoplasia, resulting in a positive molar tooth sign. (D) Cerebral magnetic resonance image of a child with Meckel–Gruber syndrome (MKS) showing severe brain malformations: occipital encephalocele and massively enlarged cerebrospinal fluid compartments. (E) An x-ray of a postaxial hexadactyly in a child with Bardet–Biedl syndrome (BBS). COACH, cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis; COMA, congenital oculomotor apraxia; MSS, Mainzer–Saldino syndrome.

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    Onset of ESRD is depending on the underlying genotype. Survival free of ESRD among children with NPHP1 and without NPHP1 in the Nephronophthisis Registry. Kaplan–Meier analysis of kidney survival highlights the difference between children with NPHP1 (n=58) and children without NPHP1 (n=85). (A) Although in 90% of children with NPHP1, kidney function declined rapidly between 8 and 16 years of age, within the children without NPHP1, there was no uniform pattern regarding the development of CKD. (B) Although most children with NPHP3 and children with IFT140 developed ESRD in infancy or early childhood, in children with NPHP4 and children with NPHP5/IQCB1, (D) ESRD only occurred late within the second decade of life. (C) The data on children with NPHP6/CEP290 and children with NPHP11/TMEM67, however, were inconclusive, including patients with early as well as late ESRD.

Tables

  • Figures
  • Additional Files
    • View popup
    Table 1.

    Phenotypic presentation of 152 children with suspected isolated nephronophthisis or nephronophthisis-related ciliopathies in the Nephronophthisis Registry

    PhenotypeNPHP1, n=60All Genotypes Other Than NPHP1, n=92NPHP3, n=4NPHP4, n=5NPHP5/IQCB1, n=5NPHP6/CEP290, n=5NPHP11/TMEM67, n=6IFT140, n=4
    Kidney
     Onset of renal symptoms, yr3–160–76–1413–257–172–153–16
     Polyuria, %633650604020170
     Urinary concentrating deficiency, %402625404020170
     Proteinuria, %323925202001775
     Hematuria, %1811000000
     Anemia, %88551008080605050
     Failure to thrive, %2026040040330
     Growth retardation, %283250600603350
    Liver
     Onset of liver symptoms, yr10–130–10---1–38
     Total, %8a41a10000010025
     Hepatosplenomegaly, %3291000001000
     Elevated liver enzymes, %52710000010025
     Cholestasis, %01050000330
     Thrombopenia, %31150000330
     Ascites, %032500000
     Esophageal varices, %080000170
     Hepatic pruritus, %2250000170
    CNS
     Onset of neurologic symptoms, yr1–12-690–10–38
     Total, %25b47b020201008325
     Developmental delay, %1940020201008325
     Seizures, %780020000
     Ataxia, %821020080830
     Cerebellar vermis hypoplasia, %320000100500
     Muscle weakness, %340000330
     Microcephaly, %01000000
    Eyes
     Onset of eye symptoms, yr1–179-0–10–70–11–9
     Total, %415525010010083100
     Visual impairment, %23c41c2501001005075
     Nystagmus, %1226001001003375
     COMA, %1090000500
     Night blindness, %21100600050
     Retinitis pigmentosa, %51800100200100
     Visual field restriction, %5120010000100
     Astigmatism, %1712250400170
     Strabism, %8900200330
     Cataract, %220020000
     Coloboma, %070000330
    • For practical reasons, we stratified the cohort into children with NPHP1 (n=60) and children without NPHP1 (n=92). Cell contents are the percentages of participants in a given column (genotype) for which the symptom listed in the row header was reported or the ranges of ages over which these symptoms initially presented. Whenever possible, we further classified the children without NPHP1 according to their gene defect. CNS, central nervous system; COMA, congenital oculomotor apraxia.

    • ↵a Statistical significance: liver involvement was significantly more frequent in the non-NPHP1 group compared with the NPHP1 cohort (41% versus 8%; P<0.001).

    • ↵b Statistical significance: presence of neurologic symptoms was significantly more frequent in the non-NPHP1 group compared with the NPHP1 cohort (47% versus 25%; P<0.01).

    • ↵c Statistical significance: visual loss was significantly more frequent in the non-NPHP1 group compared with the NPHP1 cohort (41% versus 23%; P=0.02).

    • View popup
    Table 2.

    Genotype-phenotype correlation of 89 children in the Nephronophthisis Registry carrying mutations in various ciliary genes

    GenotypeSenior LøkenJoubertCOACHCOMAJeune/MSSCKDAge at ESRD, yr (1)Liver InvolvementOcular InvolvementCNS InvolvementAirways InvolvementSkeletal Involvement
    NPHP1, n=6075—8—9811.4±2.4 (n=43)8412582
    NPHP3, n=4—————1000.7; 4; 8; 10 (n=4)10025—50—
    NPHP4, n=5—————10014 (n=1)——20——
    NPHP5/IQCB1, n=5100————10014; 16; 16; 27 (n=4)—10020——
    NPHP6/CEP290, n=5—100———607; 21 (n=2)—10010040—
    NPHP11/TMEM67, n=6—333317—673; 6; 8; 18 (n=4)1008383——
    IFT140, n=4————1001007; 10 (n=2)2510025—100
    • Cell contents are the percentages of participants in a given row (genotype) for which the phenotype listed in the column header was observed or the ages (as means±SD or lists of individual ages) at which ESRD developed. COACH, cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis; COMA, congenital oculomotor apraxia; MSS, Mainzer–Saldino syndrome; CNS, central nervous system; —, 0% of patients.

Additional Files

  • Figures
  • Tables
  • Supplemental Data

    • Supplemental Data
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 12 (12)
Clinical Journal of the American Society of Nephrology
Vol. 12, Issue 12
December 07, 2017
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies
Jens König, Birgitta Kranz, Sabine König, Karl Peter Schlingmann, Andrea Titieni, Burkhard Tönshoff, Sandra Habbig, Lars Pape, Karsten Häffner, Matthias Hansen, Anja Büscher, Martin Bald, Heiko Billing, Raphael Schild, Ulrike Walden, Tobias Hampel, Hagen Staude, Magdalena Riedl, Norbert Gretz, Martin Lablans, Carsten Bergmann, Friedhelm Hildebrandt, Heymut Omran, Martin Konrad
CJASN Dec 2017, 12 (12) 1974-1983; DOI: 10.2215/CJN.01280217

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies
Jens König, Birgitta Kranz, Sabine König, Karl Peter Schlingmann, Andrea Titieni, Burkhard Tönshoff, Sandra Habbig, Lars Pape, Karsten Häffner, Matthias Hansen, Anja Büscher, Martin Bald, Heiko Billing, Raphael Schild, Ulrike Walden, Tobias Hampel, Hagen Staude, Magdalena Riedl, Norbert Gretz, Martin Lablans, Carsten Bergmann, Friedhelm Hildebrandt, Heymut Omran, Martin Konrad
CJASN Dec 2017, 12 (12) 1974-1983; DOI: 10.2215/CJN.01280217
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Overview
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

Original Articles

  • Variability in Culture-Negative Peritonitis Rates in Pediatric Peritoneal Dialysis Programs in the United States
  • Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese
  • Trends in Discard of Kidneys from Hepatitis C Viremic Donors in the United States
Show more Original Articles

Cystic Kidney Disease

  • Multicenter Study of Long-Term Safety of Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease
  • Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement
  • A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials
Show more Cystic Kidney Disease

Cited By...

  • The renal inflammatory network of nephronophthisis
  • Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy
  • Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood
  • Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney
  • The Underestimated Burden of Monogenic Diseases in Adult-Onset ESRD
  • A Perspective on Inherited Kidney Disease: Lessons for Practicing Nephrologists
  • Google Scholar

Similar Articles

Related Articles

  • A Perspective on Inherited Kidney Disease
  • PubMed
  • Google Scholar

Keywords

  • Nephronophthisis (NPH)
  • Nephronophthisis related ciliopathy
  • Joubert-like syndromes
  • Senior-Løken syndrome
  • Bardet-Biedl syndrome
  • Congenital oculomotor apraxia
  • COACH syndrome
  • Mainzer-Saldino syndrome
  • NEPHREG registry
  • adolescent
  • Genetic Heterogeneity
  • prevalence
  • Cross-Sectional Studies
  • Nephronophthisis, familial juvenile
  • Kidney Diseases, Cystic
  • Homozygote
  • Kidney Failure, Chronic
  • mutation
  • registries
  • Ciliopathies

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire